Many of the most prevalent diseases in humans including ischemia, stroke, epilepsy, asthma and allergy are all believed to be related to the phenomenon of cell hyperexcitation, a term used herein to denote supranormal intracellular enzyme activity.
Epilepsy in particular is characterized by transitory high levels of abnormal neurological activity or seizures, referred to as the ictal state. The interictal state is manifested by a period of relative quiescence. Types of seizures include partial, or focal seizures, which are restricted to a particular locus within the brain; and generalized seizures, which can result in abnormal activity throughout the brain. Generalized seizures include tonic-clonic, or grand mal, seizures, in which the entire body undergoes convulsions. Left untreated, epilepsy can degenerate into status epilepticus a potentially fatal neurological emergency [Antiepileptic Drugs; eds. R. H. Levy, R. H. Mattson and B. S. Meldrum; 4.sup.th Edition, Raven Press, NY, N.Y.].
Because of the potential dangers of epilepsy, many different types of therapeutic modalities have been proposed. However, the effective treatment of epilepsy has been hampered by the side effects of many medications. For example, some anti-epileptic medications, such as phenobarbital, are sedating [Antiepileptic Drugs; eds. R. H. Levy, R. H. Mattson and B. S. Meldrum; 4.sup.th Edition; Raven Press, NY, N.Y.; p. 130-131]. Others, such as valproic acid, are hepatotoxic, have teratogenic effects and may interact with other therapeutic drugs. Certain anti-epileptic medications have dangerous systemic effects, such as potentially fatal aplastic anemia, hepatotoxicity and connective tissue abnormalities [Antiepileptic Drugs; eds. R. H. Levy, R. H. Mattson and B. S. Meldrum; 4.sup.th Edition; Raven Press, NY, N.Y.; p. 130-131]. Such dangerous side effects are a direct consequence of drugs which have broad systemic delivery and absorption.
These dangerous side effects restrict the therapeutic use of otherwise effective drugs. For example, valproic acid is highly effective against several types of generalized seizures, including absence, generalized tonic-clonic and myoclonic seizures [Antiepileptic Drugs; eds. R. H. Levy, R. H. Mattson and B. S. Meldrum; 4.sup.th Edition, Raven Press, NY, N.Y.]. Valproic acid was clinically shown to be effective against epilepsy in many patients who have proven to be refractory to other treatments. Valproic acid has also been found to be an effective prophylactic against migraines and bipolar disorders, as well as in the treatment of central pain [Shelton C E, Connelly J F, "Valproic acid: a migraine prophylaxis alternative", Ann Pharmacother, 30:865-866, 1996; Cutrer F M, and Moskowitz M A, "The actions of valproate and neurosteroids in a model of trigeminal pain", Headache, 36:579-585, 1996; and Keck P E Jr, McElroy S L and Strakowski S M, "New developments in the pharmacologic treatment of schizoaffective disorder" J Clin Psychiatry, 57 Suppl 9:41-48., 1996). Unfortunately, as noted above, valproic acid and many of its analogs have a number of side effects, including: tremors, sedation, irritability, neutropenia, bone marrow suppression, hepatotoxicity, teratogenic effects, and metabolic disturbances including hyperammonemia-a condition which itself can cause seizures [Antiepileptic Drugs; eds. R. H. Levy, R. H. Mattson and B. S. Meldrum; 4.sup.th Edition, Raven Press, NY, N.Y.]. Clearly, developing a form of valproic acid which is substantially free of these effects would be highly useful.
Side effects of anti-epileptic medications can be divided into two general groups. The first group includes unwanted neurological effects, such as sedation. The second, and occasionally fatal, group includes systemic effects such as hepatic dysfunction and aplastic anemia. Both groups of side effects result from a combination of delivery of the active molecule to tissues other than diseased neurons and the ability of the active molecule to alter the normal function of these tissues. Thus, both groups of side effects are amenable to amelioration by restriction of the delivery of the active drug molecule only to diseased cells to be treated and by modification of the pharmacophore to eliminate effects on normal tissues.
One strategy which limits the delivery of the active drug molecule to the desired site of action is disclosed in International Patent Application WO 94/22483, filed Mar. 30, 1994, herein incorporated by reference. According to this disclosure, the drug is selectively activated in those diseased cells which exhibit specific enzyme hyperactivity. The pharmacologically active molecule is administered in the form of an inactive prodrug which is designed to be cleaved preferentially by the excess enzyme activity, so that the pharmacologically active molecule accumulates at the diseased site rather than in healthy cells. Such targeting was shown to effectively treat the pathological state of the diseased cells, with far fewer effects on the normal cells.
Although many different types of prodrugs are possible, WO 94/22483 disclosed cell permeable prodrugs, composed of a pharmacologically active compound covalently bound to a lipophilic moiety which facilitates intracellular transport of the prodrug. Hereinafter the term "prodrug" denotes a molecule which has either little or no pharmacological activity of the active compound. The active compound will exert its therapeutic effects after it is released from the prodrugs of the invention by the action of intracellular enzymes. The covalent bond of these prodrugs are scission sensitive to enzymes that are hyperactive in the cells that are affected, thereby providing selective activation of the pharmacological compound in the diseased cells.
One group of intracellular enzymes of particular relevance in the pathogenesis of epilepsy and ischemic injury are the phospholipases, especially phospholipase A.sub.2 (PLA.sub.2). In excitatory disorders such as epilepsy, phopholipase activity increases many fold.
Phospholipase A.sub.2 demonstrates a sustained increase in activity during the ictal and postictal period, although other phospholipases may also be involved in the pathogenesis of epilepsy. WO 94/22483 discloses a prodrug form of valproic acid, called TVA, which is scission-sensitive to PLA.sub.2. Chemically, TVA comprises valproic acid covalently linked as an ester to a phosphatidylcholine moiety ROCH.sub.2 --CH(OH)--CH.sub.2 O--(PO.sub.2)--O(CH.sub.2).sub.2 N(CH.sub.3).sub.3, wherein R is hexadecanoyl. Clearly such prodrugs can be activated within the body and exert a pharmacological effect. In a mouse experimental model, TVA was shown to have significant anticonvulsant activity and to be more than 10 times as potent as sodium valproate.
A second strategy for both enhancing efficacy and eliminating side effects of drugs is the modification or alteration of a "lead compound" to produce a novel molecule which has the desired therapeutic effect without the unwanted side effects. Such an approach is widely used in drug design. Unfortunately, rational drug design is limited by the lack of knowledge with regard to biological drug interactions, and in particular the lack of three-dimensional structures for specific cell components, such as receptors, with which the drugs interact. Thus, although valproic acid has been widely studied, altered forms of this drug have not yet been found which eliminate the side effects.
There is therefore a need for, and it would be highly advantageous to have, analogs of valproic acid which substantially lack systemic side effects.